Mammalian development requires the specification of over 200 unique cell types from a single totipotent cell. This challenge is all the more impressive as each of these cell types carries the same genetic information, yet is able to establish and maintain the unique gene expression profile giving rise to its cellular identity. Epigenetic changes in chromatin state allow cells to integrate and remember signals received over multiple cell generations, however the molecular basis of this cellular memory has remained elusive.

In addition to post-translational modification of histone proteins, chromatin remodeling through incorporation of histone variants adds to the complexity of epigenetic regulation. For example, the histone variant H3.3 differs from canonical H3 by only 4-5 amino acids, yet displays distinct genomic and developmental enrichment properties. While long associated with genome activation, our recent studies have revealed an unexpected role for the histone variant H3.3 in the establishment of silenced chromatin states, with important implications for maintenance of cellular identity and genome stability. Our work demonstrates that the incorporation of a histone variant can directly impact histone post-translational modification states and therefore local genome regulation. However, many questions remain. How are chromatin-associated proteins recruited to appropriate genomic locations at the appropriate time? How do cells interpret local environment to establish chromatin states resulting in appropriate gene expression profiles in any given tissue type? How are these signals integrated such that chromatin states are “remembered” over time?

We hypothesize that chromatin allows cells to integrate and act upon local signaling events to control cell fate decisions during organismal development as well as in normal tissue homeostasis in adult organisms. The long-term goal of our research program is to understand the contribution of chromatin variation to the establishment of gene expression programs required for cell specification during differentiation and the epigenetic memory of cellular identity. These questions are of fundamental importance to studies of differentiation and development, and by extension, the pathologies that arise when misregulation occurs.